Use of substituted amidino compounds in the treatment of chronic obstructive pulmonary disease

ABSTRACT

Use in medicaments for the treatment of chronic obstructive pulmonary disease of compounds of formula                    
     wherein the C(═NH)—NHR 3  group may be in tautomeric or isomeric form, or a pharmaceutically acceptable salt thereof, in which: 
     R 1  is amino which is mono- or disubstituted by a substituent selected from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon radical, an aromatic radical, and a cycloaliphatic hydrocarbon radical or is amino which is disubstituted by a divalent aliphatic hydrocarbon radical or a said radical interrupted by oxygen; 
     R 2  is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy or is hydroxy which is etherified by an aliphatic, araliphatic or aromatic alcohol or by an aliphatic alcohol which is substituted by carboxy, by esterified carboxy or by amidated carboxy or which is esterified by an aliphatic or araliphatic carboxylic acid; 
     R 3  is hydrogen or an acyl radical which is derived from an organic carbonic acid, an organic carboxylic acid, a sulfonic acid, or a carbamic acid; 
     X 1  and X 3 , independently or one another, are oxygen (—O—) or sulphur (—S—); and X 2  is a divalent aliphatic hydrocarbon radical which may be interrupted by an aromatic radical; 
     wherein the phenyl rings of formula I may be, independently or one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; 
     wherein aryl in the above definitions may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; 
     wherein a cycloaliphatic hydrocarbon radical may be substituted by an aliphatic radical.

This is a continuation of U.S. patent application Ser. No. 09/435,943filed Nov. 9, 1999, pending, which is a continuation of U.S. patentapplication Ser. No. 09/210,634, filed Dec. 11, 1998, abandoned, whichis a continuation of U.S. Patent Application No. 60/112,002, filed Dec.12, 1997, which is a continuation of U.S. patent application No. Ser.08/989,367, filed Dec. 12, 1997, now abandoned.

This invention relates to the use of organic compounds, particularlysubstituted amidino compounds, in the treatment of chronic obstructiverespiratory diseases, particularly chronic obstructive pulmonary disease(COPD), including emphysema, cystic fibrosis and, especially, chronicbronchitis.

COPD is one of the major causes of death and disability in the USA andEurope and there are no effective therapies currently available whichprevent progression of the disease. The most common causal mechanism iscigarette smoking, which leads to chronic bronchitis. About 15% ofsmokers develop progressive airflow limitation, which is largely due toemphysema.

The invention provides, in one aspect, the use, for the preparation of amedicament for the treatment of chronic obstructive pulmonary disease,of a pharmacologically active compound of formula

wherein the C(═NH)—NHR₃ group may be in tautomeric or isomeric form, ora pharmaceutically acceptable salt thereof, in which:

R₁ is amino which is mono- or disubstituted by a substituent selectedfrom an aliphatic hydrocarbon radical, an araliphatic hydrocarbonradical, an aromatic radical, and a cycloaliphatic hydrocarbon radicalor is amino which is disubstituted by a divalent aliphatic hydrocarbonradical or a said radical interrupted by oxygen;

R₂ is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbonradical, hydroxy or is hydroxy which is etherified by an aliphatic,araliphatic or aromatic alcohol or by an aliphatic alcohol which issubstituted by carboxy, by esterified carboxy or by amidated carboxy orwhich is esterified by an aliphatic or araliphatic carboxylic acid;

R₃ is hydrogen or an acyl radical which is derived from an organiccarbonic acid, an organic carboxylic acid, a sulfonic acid, or acarbamic acid;

X₁ and X₃, independently of one another, are oxygen (—O—) or sulphur(—S—); and X₂ is a divalent aliphatic hydrocarbon radical which may beinterrupted by an aromatic radical;

wherein the phenyl rings of formula I may be, independently of oneanother, further substituted by one or more substituents selected fromhalogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, andhydroxy which is etherified by an aliphatic alcohol or which isesterified by an aliphatic or araliphatic carboxylic acid;

wherein aryl in the above definitions may be, independently of oneanother, further substituted by one or more substituents selected fromhalogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, andhydroxy which is etherified by an aliphatic alcohol or which isesterified by an aliphatic or araliphatic carboxylic acid;

wherein a cycloaliphatic hydrocarbon radical may be substituted by analiphatic radical.

In another aspect, the invention provides pharmacologically activecompounds of formula I and pharmaceutically acceptable salts thereof foruse in the treatment of chronic obstructive pulmonary disease.

In a further aspect, the invention provides a method for the treatmentof chronic obstructive pulmonary disease which comprises administeringto a mammal in need of such treatment an effective amount of apharmacologically active compound of formula I, or a pharmaceuticallyacceptable salt thereof, as hereinbefore defined.

The compounds of formula I wherein the C(═NH)—NHR₃ group is intautomeric or isomeric form are represented by formula I¹

wherein R₁, R₂, R₃, X₁, X₂ and X₃ have the meanings as defined forformula I.

As compounds of formula I have a basic centre, they can thus form acidaddition salts, especially pharmaceutically acceptable salts. These areformed, for example, with inorganic acids, such as mineral acids, forexample sulfuric acid, a phosphoric or hydrohalic acid, or with organiccarboxylic acids, such as (C₁-C₄)-alkanecarboxylic acids which, forexample, are unsubstituted or substituted by halogen, for example aceticacid, such as saturated or unsaturated dicarboxylic acids, for exampleoxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalicacid, such as hydroxycarboxylic acids, for example ascorbic, glycolic,lactic, malic, tartaric or citric acid, such as amino acids, for exampleaspartic or glutamic acid, benzoic acid or with organic sulfonic acids,such as (C₁-C₄)-alkane- or arylsulfonic acids which are unsubstituted orsubstituted, for example, by halogen, for example methane- ortoluenesulfonic acid. Preferred are salts formed with hydrochloric acid,methanesulfonic acid and maleic acid, especially maleic acid.

The general definitions used below have, if not defined differently, thefollowing meanings:

An aliphatic hydrocarbon radical is, for example, lower alkyl, loweralkenyl and secondarily lower alkynyl.

An araliphatic hydrocarbon radical is, for example, optionallysubstituted phenyl-lower alkyl and secondarily phenyl-lower alkenyl andphenyl-lower alkynyl.

A cycloaliphatic hydrocarbon radical is, for example, cycloalkyl andsecondarily cycloalkenyl, which is unsubstituted or mono- orpolysubstituted, for example, disubstituted, by lower alkyl.

A divalent aliphatic hydrocarbon radical is, for example, loweralkylene.

A divalent aliphatic radical interrupted by oxygen is, for example,lower alkylene interrupted by oxygen, e.g. ethylene-O-ethylene.

A divalent aliphatic hydrocarbon radical which is interrupted by anaromatic radical is, for example, lower alkylene-phenylene-loweralkylene or lower alkylene-naphthylene-lower alkylene.

An aliphatic alcohol is, for example, a lower alkanol or lower alkenol,and an araliphatic alcohol is, for example, a phenyl-lower alkanol, forexample benzyl alcohol.

Hydroxy which is etherified by an aliphatic or araliphatic alcohol is,for example, lower alkoxy or lower alkenyloxy and phenyl-lower alkoxy.

Hydroxy etherified by an aliphatic alcohol substituted by carboxy,esterified carboxy or amidated carboxy is, for example, lower alkoxysubstituted by carboxy, by lower alkoxycarbonyl, by aryl-loweralkoxycarbonyl, by aminocarbonyl or by mono- or di-loweralkylaminocarbonyl.

An aliphatic carboxylic acid is, for example, a lower alkanoic or loweralkenoic acid, and an araliphatic carboxylic acid is, for example, aphenyl-lower alkanoic acid.

Hydroxy which is esterified by an aliphatic or araliphatic carboxylicacid is, for example, lower alkanoyloxy, lower alkenoyloxy orphenyl-lower alkanoyloxy.

An acyl radical which is derived from an organic carboxylic acid is, forexample, lower alkanoyl, phenyl-lower alkanoyl or unsubstituted orsubstituted aroyl, such as benzoyl, naphthoyl, indanoyl or fluorenoyl,or heteroaroyl such as pyridylcarbonyl, thienylcarbonyl,pyrrolylcarbonyl, furanylcarbonyl and imidazolylcarbonyl.

An acyl radical which is derived form an organic carbonic acid is, forexample, alkoxycarbonyl or alkenyloxycarbonyl which in each case areunsubstituted or substituted by an aromatic radical or iscycloalkoxycarbonyl which unsubstituted or substituted by lower alkyl.

An acyl radical which is derived from a sulfonic acid is, for example,alkanesulfonyl, arylalkanesulfonyl, cycloalkanesulfonyl or arylsulfonyl.

An acyl radical which is derived from a carbamic acid is, for example,amino-carbonyl which is substituted by alkyl, arylalkyl or aryl.

An aromatic radical is, for example, unsubstituted or substituted suchas monosubstituted or polysubstituted, for example, disubstituted orsecondarily trisubstituted carbocyclic aryl, such as phenyl, naphthyl,indanyl or fluorenyl, or heterocyclic aryl, such as pyridyl, thienyl,pyrrolyl, furanyl, and imidazolyl.

Aryl represents preferably monocarbocyclic aryl, advantageouslyoptionally substituted phenyl, such being phenyl or phenyl substitutedby e.g. lower alkyl, lower alkoxy, halogen or trifluoromethyl.

The phenyl rings of formulae I and I¹ as well as aromatic radicalsreferred to before and hereafter are generally unsubstituted or furthersubstituted such as monosubstituted or polysubstituted, for exampledisubstituted or secondarily trisubstituted, in particular, for example,by a substituent selected from the group consisting of halogen,trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy,lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy,lower alkenoyloxy, and phenyl-lower alkanoyloxy. Preferably, the phenylrings of formula I and I¹ do not exhibit any additional substitutent.

Preferred positions of the following structural elements in thecorresponding phenyl ring in formula I are: positions 4 (para) or 5(meta) for —C—R₁, position 2 (ortho) or 3 (meta) for R₂, and position 4(para) for —C(═NH)—NHR₃ grouping and both tautomeric and isomeric formsare encompassed by the instant invention.

The term “substituted by one or more substituents” refers preferably toone, two or three such substituents, advantageously one or two.

The expression “lower” means that corresponding groups and compounds ineach case contain in particular not more than 7, preferably not morethan 4, carbon atoms.

Halogen is, in particular, fluorine, chlorine or bromine, andfurthermore includes iodine.

Lower alkyl is, in particular, C₁-C₇-alkyl and is, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl andfurthermore includes corresponding pentyl, hexyl and heptyl radicals.C₁-C₄-alkyl is preferred.

Lower alkenyl is, in particular, C₃-C₇-alkenyl and is, for example,2-propenyl or 1-, 2- or 3-butenyl. C₃-C₅-Alkenyl is preferred.

Lower alkynyl is, in particular, C₃-C₇-alkynyl and is preferablypropargyl.

Phenyl-lower alkyl is, in particular, phenyl-C₁-C₄-alkyl and ispreferably benzyl, 1- and 2-phenethyl, while phenyl-lower alkenyl andphenyl-lower alkynyl are, in particular, phenyl-C₂-C₅alkenyl and-alkynyl, in particular 2-phenyl-vinyl, 3-phenylallyl and3-phenylpropargyl.

Cycloalkyl is, in particular, C₃-C₇-cycloalkyl and is, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is, in particular, C₃-C₇-cycloalkenyl and is preferablycyclopent-2- or -3-enyl, or cyclohex-2- and -3-en-yl.

Lower alkylene e.g. in amino which is disubstituted by lower alkyleneis, in particular, C₂-C₆-alkylene and is, for example, butylene,pentylene, or 2,6-hexylene. Preferred is C₄-C₅-alkylene, especiallypentylene.

Lower alkylene X₂ is, in particular, C₂-C₈-alkylene, preferablystraight-chain, and is, for example, ethylene, propylene, butylene,pentylene, hexylene, heptylene and also octylene. C₄-C₇-Alkylene ispreferred, especially pentylene and also butylene, hexylene orheptylene.

Lower alkylene which is interrupted by a phenyl radical (X₂) is, inparticular, lower alkylene-phenylene-lower alkylene or loweralkylene-napthylene-lower alkylene such asC₂-C₄-alkylene-phenylene-C₂-C₄-alkylene orC₂-C₄-alkylene-napthylene-C₂-C₄-alkylene, preferably straight-chain, andis, for example, methylene-phenylene-methylene,1,2-ethylene-phenylene-1,2-ethylene, such as1,2-ethylene-1,4-phenylene-1,2-ethylene,1,3-propylene-phenylene-1,3-propylene, such as1,3-propylene-1,4-phenylene-1,3-propylene, orbutylene-phenylene-butylene radicals, also a corresponding1,2-ethylene-napthylene-1,2-ethylene radical.

C₂-C₄-alkylene-phenylene-C₂-C₄-alkylene orC₂-C₃-alkylene-napthylene-C₂-C₃-alkylene is preferred, especially1,2-ethylene-1,4-phenylene- 1,2-ethylene.

Lower alkoxy is, in particular, C₁-C₇-alkoxy and is, for example,methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy,sec-butyloxy, tert-butyloxy and furthermore includes correspondingpentyloxy, hexyloxy and heptyloxy radicals. C₁-C₄-Alkoxy is preferred.

Lower alkenyloxy is, in particular, C₃-C₇-alkenyloxy and is, forexample, allyloxy or but-2-en- or but-3-enyloxy. C₃-C₅-Alkenyloxy ispreferred.

Phenyl-lower alkoxy is, in particular, phenyl-C₁-C₄-alkoxy, such asbenzyloxy, 1- or 2-phenylethoxy, or 1-, 2- or 3-phenylpropyloxy.

Lower alkanoyloxy is, in particular, C₂-C₈-alkanoyloxy, in particular,C₂-C₅-alkanoyloxy, such as acetyloxy, propionyloxy or pivaloyloxy.

Lower alkenoyloxy is, in particular, C₃-C₈-alkenoyloxy, in particular,C₃-C₅-alkenoyloxy, such as propenoyloxy.

Phenyl-lower alkanoyloxy is, in particular, phenyl-C₂-C₈-alkanoyloxy, inparticular, phenyl-C₂-C₅-alkanoyloxy, such as phenylacetyloxy,phenylpropionloxy or phenylpivaloyloxy.

Alkoxycarbonyl is, in particular, C₂-C₁₂-alkoxycarbonyl and is, forexample, methoxy-, ethoxy-, propyloxy-pivaloxy or oxtyloxy-carbonyl.C₂-C₉-Alkoxycarbonyl is preferred.

Alkenyloxycarbonyl is, in particular, C₃-C₁₂-alkenyloxycarbonyl, forexample, allyloxycarbonyl. Preferred is C₃-C₅-alkenyloxycarbonyl.

Cycloalkyloxycarbonyl is, in particular, C₃-C₇-cycloalkyloxycarbonyl,preferred is cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.

Alkanesulfonyl is, in particular, C₁-C₇alkanesulfonyl and is, forexample, methane-, ethane-, n-propane- or isopropanesulfonyl.C₁-C₄-Alkanesulfonyl is preferred.

Arylalkanesulfonyl is, in particular, phenyl-C₁-C₇alkanesulfonyl, forexample, benzyl- or 1- and 2-phenylethan-sulfonyl.Phenyl-C₁-C₄-alkane-sulfonyl is preferred.

Cycloalkanesulfonyl is, in particular, C₃-C₇-cycloalkanesulfonyl,preferred is cyclopentanesulfonyl or cyclohexanesulfonyl.

Naphthyl is 1- or 2-naphthyl.

Indanyl is, for example, 1-, 2-, 3- or 4-indanyl.

Fluorenyl is, for example, 1-, 2-, 3-, 4- or 5-fluorenyl.

Lower alkanoyl is, in particular, C₁-C₇-alkanoyl and is, for example,formyl, acetyl, propionyl, butyryl, isobutyryl or pivavolyl.C₂-C₅-Alkanoyl is preferred.

Phenyl-lower alkanoyl is, in particular, phenyl-C₂-C₇-alkanoyl and is,for example, phenylacetyl or 2- or 3-phenylpropionyl.Phenyl-C₂-C₄-alkanoyl is preferred.

Substituted aroyl represents aroyl, such as benzoyl, which issubstituted e.g. by lower alkoxy, lower alkyl, hydroxy, hydroxymethyl orby acyloxymethyl (such as lower alkanoyloxymethyl or benzoyloxymethyl.

Naphthoyl is 1- or 2-naphthoyl.

Indanoyl is, for example, 1-, 2-, 3- or 4-indanoyl.

Fluorenoyl is, for example, 1-, 2-, 3- 4- or 5-fluorenoyl.

Esterified carboxyl represents preferably lower alkoxycarbonyl oraryl-lower alkoxycarbonyl.

Amidated carboxyl represents preferably aminocarbonyl, mono- or di-loweralkylaminocarbonyl, (mono-aryl-mono-lower alkyl)aminocarbonyl, mono- ordi-(aryl-lower alkyl)aminocarbonyl or (mono-aryl-lower alkyl-mono-loweralkyl)aminocarbonyl.

The invention relates preferably to the use of compounds of formula Iand pharmaceutically acceptable salts thereof, in which:

R₁ is amino which is mono- or disubstituted by a substituent selectedfrom lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl,phenyl-lower alkenyl, phenyl-lower alkynyl, phenyl, napthyl, indanyl,fluorenyl, cycloalkyl, and cycloalkenyl, cycloalkyl and cycloalkenyleach being unsubstituted or mono- or polysubstituted by lower alkyl, oris amino which is disubstituted by lower alkylene;

R₂ is hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-loweralkoxy, phenoxy, lower alkoxy substituted by carboxy, loweralkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl,lower alkanoyloxy, lower alkenoyloxy or phenyl-lower alkanyloxy;

R₃ is hydrogen, alkoxycarbonyl or alkenyloxycarbonyl, each of which isunsubstituted or substituted by phenyl, naphthyl, indanyl or fluorenyl,or is cycloalkoxycarbonyl being unsubstituted or mono- orpolysubstituted by lower alkyl, or is lower alkanoyl or phenyl-loweralkanoyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or isC₁-C₇-alkanesulfonyl, phenyl-C₁-C₇alkanesulfonyl,C₃-C₇-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl whichis substituted by lower alkyl, phenyl-lower alkyl or phenyl;

X₁ and X₃, independently of one another, are O or S;

X₁ is lower alkylene, lower alkylene-phenylene-lower alkylene or loweralkylene-naphthylene-lower alkylene;

wherein the phenyl rings of formula I may be, independently of oneanother, substituted by one or more substituents selected from halogen,trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy,lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy,lower alkenoyloxy and phenyl-lower alkanoyloxy;

wherein the aromatic radicals in the above definitions may be,independently of one another, substituted by one or more substituentsselected from halogen, trifluoromethyl, lower alkyl, lower alkenyl,lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-loweralkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-loweralkanoyloxy.

The invention especially relates to the use of compounds of formula Iand pharmaceutically acceptable salts thereof, in which:

R₁ is amino which is mono- or disubstituted by a substituent selectedfrom C₁-C₇-alkyl, phenyl-C₁-C₇-alkyl, phenyl and C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl being unsubstituted or mono- or polysubstituted byC₁-C₇alkyl, or is amino which is disubstituted by C₃-C₆-alkylene;

R₂ is hydrogen, hydroxy, C₁-C₇-alkoxy, C₁-C₇-alkoxy substituted bycarboxy or lower alkoxycarbonyl or phenyl-C₁-C₄ alkoxy;

R₃ is hydrogen, C₁-C₁₂-alkoxy-carbonyl, C₂-C₅-alkanoyl,phenyl-C₂-C₅-alkanoyl, benzoyl which is unsubstituted or substituted byhalogen, trifluoromethyl, C₁-C₇-alkyl, or C₁-C₇ alkoxy,C₃-C₆-cycloalkylcarbonyl which is unsubstituted or substituted byC₁-C₇-alkyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or isC₁-C₇alkanesulfonyl, phenyl-C₁-C₇alkanesulfonyl,C₃-C₇-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl whichis substituted by C₁-C₇-alkyl, phenyl-C₁-C₇-alkyl or phenyl;

X₁ and X₃ each are —O—, or furthermore are, independently of oneanother, —O— or —S—;

X₂ is C₂-C₇-alkylene or C₂-C₄-alkylene-phenylene-C₂-C₄-alkylene;

wherein the phenyl rings of formula I may be unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁-C₇-alkyl, andC₁-C₇-alkoxy;

wherein phenyl in the above definitions is unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁-C₇-alkyl, andC₁-C₇-alkoxy.

The invention especially relates to the use of compounds of formula Iand pharmaceutically acceptable salts thereof, in which —CO—R₁ islocated in position 4 (para) or 3 or 5 (meta) of the correspondingphenyl ring with respect to -X₁-; R₂- is located in position 2 (ortho)or 3 (meta) of the corresponding phenyl ring with respect to -X₁-; and—C(═NH)—NHR₃ is located in position 4 (para) of the corresponding phenylring with respect to -X₃-.

The invention especially relates to the use of compounds of formula IA

wherein the C(═NH)—NHR₃ group may be in tautomeric or isomeric form, andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino,C₁-C₄alkyl-(phenyl)amino, such as phenyl-isopropyl-amino,C₁-C₄alkyl-(phenyl-C₁-C₄-alkyl)-amino, such as methyl-benzyl-amino,di-C₃-C₆-cycloalkylamino, such as di-cyclohexylamino, which isunsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidino substitutedby C₁-C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen, C₁-C₄-alkoxy such as methoxy or C₁-C₄-alkoxy which issubstituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono-or di-lower alkylaminocarbonyl;

R₃ is hydrogen, C₁-C₁₂-alkoxycarbonyl, such as methoxycarbonyl oroctyloxycarbonyl, phenyl-C₁-C₄-alkoxycarbonyl, such asbenzyloxycarbonyl, C₂-C₅-alkanoyl, such as acetyl, benzoyl which isunsubstituted or substituted by halogen, trifluoromethyl, C₁-C₄-alkyl orby C₁-C₄-alkoxy, such as 3,4-dimethoxybenzoyl, C₃-C₆-cycloalkylcarbonylwhich is unsubstituted or substituted by C₁-C₄-alkyl, such as2-isopropyl-5-methyl-cyclohexylcarbonyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, such as pentylene;

wherein the phenyl rings of formula IA may be unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁-C₄-alkyl, andC₁-C₄-alkoxy.

The invention especially relates to the use of compounds of formula IAand pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino,C₁-C₄-alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino,C₁-C₄-alkyl-(phenyl-C₁-C₄-alkyl)-amino, such as methyl-benzyl-amino,di-C₃-C₆-cycloalkylamino, such as di-cyclohexylamino which isunsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidino substitutedby C₁-C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen, C₁-C₄-alkoxy such as methoxy or C₁-C₄-alkoxy which issubstituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- ordi-lower alkylaminocarbonyl;

R₃ is C₁-C₄alkanesulfonyl, such as methane-, ethane- orisopropanesulfonyl, phenyl-C₁-C₄-alkanesulfonyl, such as benzylsulfonyl,C₃-C₇-cycloalkane-sulfonyl, such as cyclohexanesulfonyl, orphenylsulfonyl, or is aminocarbonyl which is substituted by C₁-C₄-alkyl,phenyl-C₁-C₄-alkyl or phenyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, such as pentylene.

The invention especially relates to the use of compounds of formula IAand pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino,C₁-C₄-alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino,C₁-C₄-alkyl-(phenyl-C₁-C₄-alkyl)-amino, such as methyl-benzyl-amino,di-C₃-C₆-cycloalkylamino, such as di-cyclohexylamino which isunsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidino substitutedby C₁-C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydrogen, C₁-C₄-alkoxy such as methoxy or C₁-C₄-alkoxy substitutedby C₁-C₄-alkoxycarbonyl, such as ethoxycarbonylmethyl, or byaminocarbonyl;

R₃ is hydrogen; or R₃ is lower alkanoyl, such as acetyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, such as pentylene.

The invention further especially relates to the use of compounds offormula IA and pharmaceutically acceptable salts thereof, in which;

R₁ is di-C₁-C₄-alkylamino, such as di-isopropylamino;

R₂ is hydrogen, C₁-C₄-alkoxy such as methoxy or C₁-C₄-alkoxy substitutedby C₁-C₄-alkoxycarbonyl or by aminocarbonyl

R₃ is C₁-C₁₂-alkoxycarbonyl, such as methoxycarbonyl oroctyloxycarbonyl, phenyl-C₁-C₄-alkoxycarbonyl, such asbenzyloxycarbonyl, C₂-C₅-alkanoyl, such as acetyl, benzoyl which isunsubstituted or substituted by halogen, trifluoromethyl, C₁-C₄-alkyl,or C₁-C₄-alkoxy, such as 3,4-dimethoxybenzoyl, C₃-C₆-cycloalkylcarbonylwhich is unsubstituted or substituted by C₁-C₄-alkyl, such as2-isopropyl-5-methyl-cyclohexycarbonyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, especially pentylene.

The invention further especially relates to the use of compounds offormula IA and pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino;

R₂ is hydrogen, C₁-C₄-alkoxy such as methoxy or C₁-C₄-alkoxy substitutedby C_(l)-C₄-alkoxycarbonyl such as ethoxycarbonyl or by aminocarbonyl,

R₃ is hydrogen or C₁-C₄-alkanoyl, such as acetyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, especially pentylene.

The invention also particularly relates to the use of compounds offormula IB

wherein the C(═NH)—NHR₃ group may be in tautomeric or isomeric form, andpharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino,C₁-C₄alkyl-(phenyl)amino, such as phenyl-isopropyl-amino,C₁-C₄-alkyl-(phenyl-C₁-C₄-alkyl)-amino, such as methyl-benzyl-amino,di-C₃-C₆-cycloalkylamino, such as di-cyclohexylamino, which isunsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidino substitutedby C₁-C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydroxy or C₁-C₄-alkoxy which is substituted by carboxy, loweralkoxycarbonyl, aminocarbonyl or by mono- or di-loweralkylaminocarbonyl;

R₃ is hydrogen, C₁-C₁₂-alkoxycarbonyl, such as methoxycarbonyl oroctyloxycarbonyl, phenyl-C₁-C₄-alkoxycarbonyl, such asbenzyloxycarbonyl, C₂-C₅-alkanoyl, such as acetyl, benzoyl which isunsubstituted or substituted by halogen, trifluoromethyl, C₁-C₄-alkyl,or C₁-C₄-alkoxy, such as 3,4-dimethoxybenzoyl, C₃-C₆-cycloalkylcarbonylwhich is unsubstituted or substituted by C₁-C₄-alkyl, such as2-isopropyl-5-methyl-cyclohexylcarbonyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, such as pentylene;

wherein the phenyl rings of formula IB may be unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁-C₄-alkyl, andC₁-C₄-alkoxy.

The invention especially relates to the use of compounds of formula IBand pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino,C₁-C₄-alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino,C₁-C₄-alkyl-(phenyl-C₁-C₄-alkyl)-amino, such as methyl-benzyl-amino,di-C₃-C₆-cycloalkylamino, such as di-cyclohexylamino, which isunsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidino substitutedby C₁-C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydroxy or C₁-C₄-alkoxy which is substituted by carboxy, loweralkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl;

R₃ is C₁-C₄alkanesulfonyl, such as methane-, ethane- orisopropanesulfonyl, phenyl-C₁-C₄-alkanesulfonyl, such as benzylsulfonyl,C₃-C₇-cycloalkane-sulfonyl, such as cyclohexanesulfonyl, orphenylsulfonyl, or is aminocarbonyl which is substituted by C₁-C₄-alkyl,phenyl-C₁-C₄-alkyl or phenyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, such as pentylene.

The invention especially relates to the use of compounds of formula IBand pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino,C₁-C₄-alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino,C₁-C₄alkyl-(phenyl-C₁-C₄-alkyl)-amino, such as methyl-benzyl-amino,di-C₃-C₆-cycloalkylamino, such as di-cyclohexylamino, which isunsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidino substitutedby C₁-C₄-alkyl, such as 2-methyl-1-piperidino;

R₂ is hydroxy or C₁-C₄-alkoxy substituted by C₁-C₄-alkoxycarbonyl, suchas ethoxycarbonylmethoxy or by aminocarbonyl, such as carbamoylmethoxy;

R₃ is hydrogen; or R₃ is C₂-C₅-alkanoyl, such as acetyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, such as pentylene.

The invention further especially relates to the use of compounds offormula IB and pharmaceutically acceptable salts thereof, in which:

R₁ is di-C₁-C₄-alkylamino, such as di-ethylamino or di-isopropylamino;

R₂ is hydroxy or C₁-C₄-alkoxycarbonylmethoxy, such asethoxycarbonylmethoxy, or aminocarbonylmethoxy;

R₃ is hydrogen or C₂-C₅-alkanoyl, such as acetyl;

X₁ and X₃ are —O—;

X₂ is C₄-C₇-alkylene, especially pentylene.

Specific especially preferred compounds are those described in WO94/11341, EP 0518819, U.S. Pat. Nos. 5,451,700 and 5,488,160,particularly the Examples of those publications.

The invention relates particularly to the use of a compound of formulaIA and pharmaceutically acceptable salts thereof in which R₁ isdi-isopropylamino, R₂ is methoxy, R₃ is hydrogen, X₁ and X₃ are —O— andX₂ is pentylene and a compound of formula IB and pharmaceuticallyacceptable salts thereof in which R₁ is di-isopropylamino, R₂ ishydroxy, R₃ is hydrogen, X₁ and X₃ are —O— and X₂ is pentylene,especially the maleate salts of said compounds.

Compounds of formula I and their salts where R₂ is hydroxy etherified byan aliphatic alcohol which is substituted by carboxy, esterified carboxyor amidated carboxy and their preparation are described in WO 94/11341.Other compounds of formula I and their salts and their preparation aredescribed in EP 0518819, U.S. Pat. Nos. 5,451,700 and 5,488,160.

Compounds of formula IB may also be prepared by catalytic hydrogenationof a compound of formula

where R₁, R₂, R₃, X₁, X₂ and X₃ are as defined in formula IB, to reducethe indicated hydroxyimino group to imino, for example usingpalladium-carbon as the catalyst in a mixture of ethanol and acetic acidwhen the compound of formula IB is isolated as the acetate salt whichmay be converted if desired into other salts such as the maleate salt orinto the free amidine using known procedures.

Compounds of formula II may be prepared as described in U.S. Pat. No.5,455,274.

The maleate (2-butenedioate) salt of the compound of formula IB in whichR₁ is di-isopropylamino, R₂ is hydroxy, R₃ is hydrogen, X₁ and X₃ are—O— and X₂ is pentylene is novel per se. This salt,4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate may be prepared as described in the Examplehereinafter.

The compounds of formula I may be prepared in the form of one of thepossible isomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, optical isomers (antipodes),racemates, or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysico-chemical differences of the constituents, into the puregeometric or optical isomers, diastereoisomers, racemates, for exampleby chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g. by separationof the diastereoisomeric salts thereof, obtained with an opticallyactive acid or base, and liberating the optically active acidic or basiccompound. Racemic amidines (wherein R₃ represents hydrogen) can thus beresolved into their optical antipodes e.g. by fractional crystallizationof a salt formed with an optically active acid.

In view of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, can also be used in the form oftheir hydrates, or include other solvents used for theircrystallization.

The compounds of formula I and their salts can be administeredenterally, such as orally or rectally, by the pulmonary route, e.g. byinhalation, transdermally and parenterally to mammals, including man, inan effective amount alone or in combination with one or morepharmaceutically acceptable carriers.

The active compound may be administered in a composition containing, forexample, from about 0.1% to about 95%, such as from about 1% to about80%, from about 10% to about 80% or, preferably from about 20% to about60%, of the active compound. Examples of pharmaceutical compositions forenteral or parenteral administration are those in dose-unit forms suchas coated tablets, tablets, capsules or suppositories, as well asampoules. These are prepared in a manner known per se, for example usingconventional mixing, granulating, coating, dissolving or freeze-dryingprocesses. Thus, pharmaceutical products for oral use can be obtained bycombining the active compound with solid excipients, where appropriategranulating a mixture which is obtained, and processing the mixture orgranules, if desired or necessary, after addition of suitableauxiliaries to tablets or cores of coated tablets.

Preferred compositions for enteral or parenteral administration aretablets and gelatin capsules comprising the active ingredient togetherwith a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol; fortablets also c) binders e.g. magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose andor polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, or effervescent mixtures; and/ore) absorbants, colorants, flavors and sweeteners. Injectablecompositions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. Cores of coated tablets are provided with suitable,optionally enteric, coatings, using, inter alia, concentrated sugarsolutions which optionally contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,lacquer solutions in suitable organic solvents or solvent mixtures or,for the preparation of enteric coatings, solutions of suitable celluloseproducts such as acetyl cellulose phthalate orhydroxypropylmethylcellulose phthalate. Colorants or pigments can beadded to the tablets or coatings of coated tablets, for example, toidentify or to indicate various doses of active compound. In addition,they may also contain other therapeutically valuable substances. Saidcompositions are prepared according to conventional mixing, granulatingor coating methods, respectively, and contain about 0.1 to 75%,preferably about 1 to 50%, of the active ingredient.

A medicament, i.e. a pharmaceutical composition, suitable for pulmonaryadministration may comprise a compound of formula I or apharmaceutically acceptable salt thereof, as hereinbefore defined,optionally in admixture with a pharmaceutically acceptable carriertherefor, the compound or mixture being in inhalable form. For example,the medicament may be in the form of an aerosol, which can be preparedin accordance with well-known procedures, or in finely dividedparticulate form comprising, for example, the active ingredient infinely divided form together with a carrier such as finely dividedlactose. Such medicaments may be administered using an inhaler devicesuitable for the inhalable form, such devices being well-known in theart.

An aerosol composition suitable for use in the method of the inventionmay comprise a compound of formula I or a pharmaceutically acceptablesalt thereof in solution, or dispersed, in a propellant, which may bechosen from any of the propellants known in the art, such asfluorocarbons. The concentration of the active ingredient in thepropellant may be up to about 5% by weight, for example 0.1 to 5%, 0.1to 3%, 0.1 to 2%, 0.2 to 2%, 0.5% to 2% or 1 to 2% by weight.

An inhalable medicament in finely divided particulate form may comprisea compound of formula I or pharmaceutically acceptable salt thereofalone or together with a finely divided solid carrier such as glucose,lactose, mannitol, sorbitol, ribose, mannose, arabinose, saccharose,galactose, fructose or xylose. In such a medicament, the compound offormula I or salt thereof suitably has a median particle size of up to10 microns, preferably up to 5 microns, especially up to 3 microns.Suitably, at least 70%, preferably at least 80%, of the particlespresent in such a particulate medicament have a median particle size ofup to 10 microns, preferably up to 5 microns, especially up to 3microns.

In accordance with the foregoing, the invention also provides apharmaceutical composition comprising as active ingredient a compound offormula I, or a pharmaceutically acceptable salt thereof, ashereinbefore defined, for use in the treatment of chronic obstructivepulmonary disease.

In conjunction with another active ingredient, a compound of formula Ior a pharmaceutically acceptable salt thereof may be administered eithersimultaneously, before or after the other active ingredient, eitherseparately by the same or different route of administration or togetherin the same pharmaceutical formulation.

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration. A unit dosage for oraladministration to a mammal of about 70 kg may contain e.g. between about1 and about 1000 mg/kg per day of the active ingredient.

The effect of compounds of formula I or their pharmaceuticallyacceptable salts in the treatment of chronic obstructive pulmonarydisease can be tested in a murine model of pulmonary neutrophiliainduced by lipopolysaccharide via intranasal instillation. Bacteriallipopolysaccharide (LPS) is a macromolecular cell surface antigen ofbacteria which, when applied in vivo triggers a network of inflammatoryresponses. The main characteristics of this LPS-induced lunginflammation model, macrophage activation, tumour necrosis factor -α(TNF-α) production and neutrophil infiltration and activation, arefeatures of chronic obstructive pulmonary disease. This model causespulmonary inflammation as an acute injury which occurs after 2 to 4hours in the airway lumen, where all the inflammatory parameters can beassessed by bronchoalveolar lavage (BAL).

The compound under test is dissolved in dimethyl sulfoxide (DMSO) and tothe resulting solution is added sterile phosphate buffered saline (PBS)(50 μl). The final concentration of DMSO is 2%. Female Balb/C mice(20-25 g) are treated intranasally, under Halothane/oxygen/nitrous oxideanaesthesia, with the PBS DMSO diluent containing the compound undertest at a suitable dose (0.1-30 mg/kg) or with diluent alone and, 30minutes later, with 0.3 mg/kg of LPS (Salmonella Typhosa, Sigma). Theanimals are housed in plastic cages in an air conditioned room at 24° C.Food and water are available ad libitum. 3 hours after intranasaladministration of LPS, terminal anaesthesia is induced withpentobarbitone sodium (60 mg/kg, i.p.), the abdominal cavity is openedand the animals are exsanguinated by withdrawal of blood from a majorblood vessel.

The trachea is cannulated and bronchoalveolar lavage (BAL) is performedby injecting 4 times 0.3 ml of PBS into the lung via the trachea. Thefluid is then immediately withdrawn and the cell suspension stored onice. Total cell count is measured and cytospin preparation (ShandonScientific Ltd, Cheshire, UK) prepared. Cells are stained with Dif-Quick(Baxter Dade AG, Dudingen, Switzerland) and a differential count of 200cells performed using standard morphological criteria. The remaininglavage fluids are centrifuged at 1200 rpm for 10 minutes, thesupernatant is aliquoted and stored at −80° C.

BAL myeloperoxidase (MPO) activity is measured on fresh BAL supernatantusing a 96 well plate format colorometric assay. 50 μl of the samples,in duplicate, are mixed with 100 μl of the substrate buffer for 5minutes at room temperature (sodium phosphate 50 mM, pH 6.0 containing0.5% hexadecyltrimethylammonium bromide, 0.167 nM o-dianisidinedihydrochloride and 0.4 mM H₂O₂). The reaction is stopped with 100 μl of5% sodium azide in distilled water and the optical density (OD) read at450 nm. Results are expressed as U/ml using a standard curve establishedwith human leukocyte myeloperoxidase (Sigma).

The inhibitory effect of the compound under test on lung inflammation isshown by the reduced neutrophil count and/or reduced MPO activityobtained after administration of the compound compared with thatobtained after administration of diluent alone.

In a modification of the above procedure, the compound under test (ordiluent alone for comparative purposes) is intranasally administered asecond time at the same dosage, 6 hours after administration of LPS andthe terminal anaesthesia is carried out 18 hours after the secondadministration. Another modification of the above procedure which can beused is described by Goncalves de Moraes et al, 1996 British Journal ofPharmacology, 117, 1792-1796.

EXAMPLE

4-[5-[4-(amino(hydroxyimino)methyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamideprepared as described in U.S. Pat. No. 5,455,274 (100.76 g), 370 mL ofacetic acid, and 800 mL of ethanol are gently shaken and warmed to50-52° C. to form a slightly yellow solution. 10% palladium-carbon (13.2g) is added and the mixture is hydrogenated at 60 psi at a temperature52-54° C. for 24 hours. The hot reaction mixture is filtered through acelite and the filter cake is washed twice with 75 mL of 2:1ethanol/acetic acid. The solvents are then removed in vacuo at 75° C.Toluene (200 mL) is added to the residue and the solvents are evaporatedin vacuo. This is repeated a second time to remove trace amounts ofacetic acid and ethanol. To the residue is added 10 g of activatedcharcoal and 50 mL of 2-propanol, and the mixture is heated to 75° C.The slurry is filtered hot and washed twice with 50 mL of 2-propanol.4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamidemonoacetate is crystallized from 2-propanol as the product, m.p.197-199° C.

CHN calculated for C₂₇H₃₈N₃O₆ Theory: %C: 64.78 %H: 7.65 %N: 8.40 Found:%C: 64.80 %H: 8.10 %N: 8.13

4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamidemonoacetate (75.24 g) is suspended in 550 mL of anhydrous ethanol (550mL) and stirred under a nitrogen atmosphere and heated to 75° C. Asolution of 34.82 g of maleic acid in 75 mL of water is heated to 75° C.and rapidly added to the mixture. Then 7 g of activated carbon is added,and the black slurry is heated to 80° C. and filtered through a celitelayer. The filter-cake is washed with ethanol/water (85 ml/15 mL), andcooled overnight to room temperature. The reaction mixture is cooled to3˜5° C. for 2 hours and4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide(Z)-2-butenedioate (1:1) is collected as white crystals, m.p. 212° C.

CHN calculated for C₂₉H₃₉N₃O₈ Theory: %C: 62.46 %H: 7.05 %N: 7.54 Found:%C: 62.20 %H: 6.92 %N: 7.38

What is claimed is:
 1. A method for the treatment of chronic obstructivepulmonary disease which comprises administering to a mammal in need ofsuch treatment an effective amount of a pharmacologically activecompound of formula

wherein the C(═NH)—NHR₃ group may be in tautomeric or isomeric form; ora pharmaceutically acceptable salt thereof, in which: R₁ is amino whichis mono- or disubstituted by a substituent selected from an aliphatichydrocarbon radical, an araliphatic hydrocarbon radical, an aromaticradical, and a cycloaliphatic hydrocarbon radical or is amino which isdisubstituted by a divalent aliphatic hydrocarbon radical or a saidradical interrupted by oxygen; R is hydrogen, halogen, trifluoromethyl,an aliphatic hydrocarbon radical, hydroxy or is hydroxy which isetherified by an aliphatic, araliphatic or aromatic alcohol or by analiphatic alcohol which is substituted by carboxy, by esterified carboxyor by amidated carboxy or which is esterified by an aliphatic oraraliphatic carboxylic acid; R₃ is hydrogen or an acyl radical which isderived from an organic carbonic acid, an organic carboxylic acid, asulfonic acid, or a carbamic acid; X₁ and X₃, independently of oneanother, are oxygen (—O—) or sulphur (—S—); and X₂ is a divalentaliphatic hydrocarbon radical which may be interrupted by an aromaticradical; wherein the phenyl rings of formula I may be, independently ofone another, further substituted by one or more substituents selectedfrom halogen, trifluoromethyl, an aliphatic hydrocarbon radical,hydroxy, and hydroxy which is etherified by an aliphatic alcohol orwhich is esterified by an aliphatic or araliphatic carboxylic acid;wherein aryl in the above definitions may be, independently of oneanother, further substituted by one or more substituents selected fromhalogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, andhydroxy which is etherified by an aliphatic alcohol or which isesterified by an aliphatic or araliphatic carboxylic acid; wherein acycloaliphatic hydrocarbon radical may be substituted by an aliphaticradical.
 2. A method according to claim 1, in which: R₁ is amino whichis mono- or disubstituted by a substituent selected from lower alkyl,lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl,phenyl-lower alkynyl, phenyl, napthyl, indanyl, fluorenyl, cycloalkyl,and cycloalkenyl, cycloalkyl and cycloalkenyl each being unsubstitutedor mono- or polysubstituted by lower alkyl, or is amino which isdisubstituted by lower alkylene; R₂ is hydrogen, halogen,trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy,lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, loweralkoxy substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl ormono- or di-lower alkylaminocarbonyl, lower alkanoyloxy, loweralkenoyloxy or phenyl-lower alkanyloxy; R₃ is hydrogen, alkoxycarbonylor alkenyloxycarbonyl, each of which is unsubstituted or substituted byphenyl, naphthyl, indanyl or fluorenyl, or is cycloalkoxycarbonyl beingunsubstituted or mono- or polysubstituted by lower alkyl, or is loweralkanoyl or phenyl-lower alkanoyl, or is benzoyl, naphthoyl, indanoyl orfluorenoyl, or is C₁-C₇-alkanesulfonyl, phenyl-C₁-C₇alkanesulfonyl,C₃-C₇-cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl whichis substituted by lower alkyl, phenyl-lower alkyl or phenyl; X₁ and X₃,independently of one another, are O or S; and X₂ is lower alkylene,lower alkylene-phenylene-lower alkylene or loweralkylene-naphthylene-lower alkylene; wherein the phenyl rings of formulaI may be, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, lower alkyl, loweralkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy,phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy andphenyl-lower alkanoyloxy; wherein the aromatic radicals in the abovedefinitions may be, independently of one another, substituted by one ormore substituents selected from halogen, trifluoromethyl, lower alkyl,lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy,phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy andphenyl-lower alkanoyloxy.
 3. A method according to claim 1, in which: R₁is amino which is mono- or disubstituted by a substituent selected fromC₁-C₇-alkyl, phenyl-C₁-C₇-alkyl, phenyl and C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl being unsubstituted or mono- or polysubstituted byC₁-C₇alkyl, or is amino which is disubstituted by C₃-C₆-alkylene; R₂ ishydrogen, hydroxy, C₁-C₇-alkoxy, C₁-C₇-alkoxy substituted by carboxy orlower alkoxycarbonyl or phenyl-C₁-C₄ alkoxy; R₃ is hydrogen,C₁-C₁₂-alkoxy-carbonyl, C₂-C₅-alkanoyl, phenyl-C₂-C₅-alkanoyl, benzoylwhich is unsubstituted or substituted by halogen, trifluoromethyl,C₁-C₇-alkyl, or C₁-C₇ alkoxy, C₃-C₆-cycloalkylcarbonyl which isunsubstituted or substituted by C₁-C₇-alkyl, or is benzoyl, naphthoyl,indanoyl or fluorenoyl, or is C₁-C₇alkanesulfonyl,phenyl-C₁-C₇alkanesulfonyl, C₃-C₇-cycloalkanesulfonyl, orphenylsulfonyl, or is aminocarbonyl which is substituted by C₁-C₇-alkyl,phenyl-C₁-C₇-alkyl or phenyl; X₁ and X₃ each are —O—, or furthermoreare, independently of one another, —O— or —S—; and X₂ is C₂-C₇-alkyleneor C₂-C₄-alkylene-phenylene-C₂-C₄-alkylene; wherein the phenyl rings offormula I may be unsubstituted or, furthermore, independently of oneanother, substituted by one or more substituents selected from halogen,trifluoromethyl, C₁-C₇-alkyl, and C₁-C₇-alkoxy; wherein phenyl in theabove definitions is unsubstituted or, furthermore, independently of oneanother, substituted by one or more substituents selected from halogen,trifluoromethyl, C₁-C₇-alkyl, and C₁-C₇-alkoxy.
 4. A method according toclaim 1, in which —CO—R₁ is located in position 4 (para) or 3 or 5(meta) of the corresponding phenyl ring with respect to -X₁—; R₂— islocated in position 2 (ortho) or 3 (meta) of the corresponding phenylring with respect to —X₁—; and —C(═NH)—NHR₃ is located in position 4(para) of the corresponding phenyl ring with respect to —X₃—.
 5. Amethod according to claim 1, in which the compound of formula I is offormula IA

wherein the C(═NH)—NHR₃ group may be in tautomeric or isomeric form, andin which: R₁ is di-C₁-C₄-alkylamino, C₁-C₄alkyl-(phenyl)amino,C₁-C₄alkyl-(phenyl-C₁-C₄-alkyl)-amino, di-C₃-C₆-cycloalkylamino, whichis unsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidinosubstituted by C₁-C₄-alkyl; R₂ is hydrogen, C₁-C₄-alkoxy or C₁-C₄-alkoxywhich is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl orby mono- or di-lower alkylaminocarbonyl; R₃ is hydrogen,C₁-C₁₂-alkoxycarbonyl, phenyl-C₁-C₄-alkoxycarbonyl, C₂-C₅-alkanoyl,benzoyl which is unsubstituted or substituted by halogen,trifluoromethyl, C₁-C₄-alkyl or by C₁-C₄-alkoxy,C₃-C₆-cycloalkylcarbonyl which is unsubstituted or substituted byC₁-C₄-alkyl; X₁ and X₃ are —O—; X₂ is C₄-C₇-alkylene; wherein the phenylrings of formula IA may be unsubstituted or, furthermore, independentlyof one another, substituted by one or more substituents selected fromhalogen, trifluoromethyl, C₁-C₄-alkyl, and C₁-C₄-alkoxy.
 6. A methodaccording to claim 5, in which: R₁ is di-C₁-C₄-alkylamino,C₁-C₄-alkyl-(phenyl)-amino, C₁-C₄-alkyl-(phenyl-C₁-C₄-alkyl)-amino,di-C₃-C₆-cycloalkylamino, which is unsubstituted or substituted byC₁-C₄-alkyl, or 1-piperidino substituted by C₁-C₄-alkyl; R₂ is hydrogen,C₁-C₄-alkoxy or C₁-C₄-alkoxy substituted by C₁-C₄-alkoxycarbonyl; R₃ ishydrogen; or R₃ is lower alkanoyl; X₁ and X₃ are —O—; and X₂ isC₄-C₇-alkylene.
 7. A method according to claim 5, in which: R₁ isdi-C₁-C₄-alkylamino; R₂ is hydrogen, C₁-C₄-alkoxy or C₁-C₄-alkoxysubstituted by C₁-C₄-alkoxycarbonyl or by aminocarbonyl; R₃ isC₁-C₁₂-alkoxycarbonyl, phenyl-C₁-C₄-alkoxycarbonyl, C₂-C₅-alkanoyl,benzoyl which is unsubstituted or substituted by halogen,trifluoromethyl, C₁-C₄-alkyl, or C₁-C₄-alkoxy, C₃-C₆-cycloalkylcarbonylwhich is unsubstituted or substituted by C₁-C₄-alkyl; X₁ and X₃ are —O—;and X₂ is C₄-C₇-alkylene.
 8. A method according to claim 5, in which: R₁is di-C₁-C₄-alkylamino; R₂ is hydrogen, C₁-C₄-alkoxy or C₁-C₄-alkoxysubstituted by C₁-C₄-alkoxycarbonyl or by aminocarbonyl; R₃ is hydrogenor C₁-C₄-alkanoyl; X₁ and X₃ are —O—; and X₂ is C₄-C₇-alkylene.
 9. Amethod according to claim 5, in which R₁ is di-isopropylamino, R₂ ismethoxy, R₃ is hydrogen, X₁ and X₃ are —O— and X₂ is pentylene.
 10. Amethod according to claim 1, in which the compound of formula I is offormula IB

wherein the C(═NH)—NHR₃ group may be in tautomeric or isomeric form, andin which: R₁ is di-C₁-C₄-alkylamino, C₁-C₄alkyl-(phenyl)amino,C₁-C₄-alkyl-(phenyl-C₁-C₄-alkyl)-amino, di-C₃-C₆-cycloalkylamino, whichis unsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidinosubstituted by C₁-C₄-alkyl; R₂ is hydroxy or C₁-C₄-alkoxy which issubstituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono-or di-lower alkylaminocarbonyl; R₃ is hydrogen, C₁-C₁₂-alkoxycarbonyl,phenyl-C₁-C₄-alkoxycarbonyl, C₂-C₅-alkanoyl, benzoyl which isunsubstituted or substituted by halogen, trifluoromethyl, C₁-C₄-alkyl,or C₁-C₄-alkoxy, C₃-C₆-cycloalkylcarbonyl which is unsubstituted orsubstituted by C₁-C₄-alkyl; X₁ and X₃ are —O—; and X₂ is C₄-C₇-alkylene;wherein the phenyl rings of formula IB may be unsubstituted or,furthermore, independently of one another, substituted by one or moresubstituents selected from halogen, trifluoromethyl, C₁-C₄-alkyl, andC₁-C₄-alkoxy.
 11. A method according to claim 10, in which: R₁ isdi-C₁-C₄-alkylamino, C₁-C₄-alkyl-(phenyl)-amino,C₁-C₄alkyl-(phenyl-C₁-C₄-alkyl)-amino, di-C₃-C₆-cycloalkylamino, whichis unsubstituted or substituted by C₁-C₄-alkyl, or 1-piperidinosubstituted by C₁-C₄-alkyl; R₂ is hydroxy or C₁-C₄-alkoxy substituted byC₁-C₄-alkoxycarbonyl, or by aminocarbonyl; R₃ is hydrogen; or R₃ isC₂-C₅-alkanoyl; X₁ and X₃ are —O—; and X₂ is C₄-C₇-alkylene.
 12. Amethod according to claim 10, in which: R₁ is di-C₁-C₄-alkylamino; R₂ ishydroxy or C₁-C₄-alkoxycarbonylmethoxy, or aminocarbonylmethoxy; R₃ ishydrogen or C₂-C₅-alkanoyl; X₁ and X₃ are —O—; and X₂ is C₄-C₇-alkylene.13. A method according to claim 10, in which R₁ is di-isopropylamino, R₂is hydroxy, R₃ is hydrogen, X₁ and X₃ are —O— and X₂ is pentylene.
 14. Amethod according to claim 1, in which the compound of formula I or saltthereof is administered in combination with a pharmaceuticallyacceptable carrier.
 15. A method according to claim 1, in which thedisease is chronic bronchitis.
 16. A method according to claim 9, inwhich the compound of formula I or salt thereof is administered incombination with a pharmaceutically acceptable carrier.
 17. A methodaccording to claim 9, in which the disease is chronic bronchitis.
 18. Amethod according to claim 13, in which the compound of formula I or saltthereof is administered in combination with a pharmaceuticallyacceptable carrier.
 19. A method according to claim 13, in which thedisease is chronic bronchitis.
 20. A medicament suitable for pulmonaryadministration comprising a compound of formula I as specified in claim1, or a pharmaceutically acceptable salt thereof, or a mixture of saidcompound or salt with a pharmaceutically acceptable carrier therefor,the compound, salt or mixture being in inhalable form.
 21. A medicamentsuitable for pulmonary administration comprising a compound of formulaIA as specified in claim 5, or a pharmaceutically acceptable saltthereof, or a mixture of said compound or salt with a pharmaceuticallyacceptable carrier therefor, the compound, salt or mixture being ininhalable form.